Multidimensional Analysis of Immune Status of Latent M. Tuberculosis Infection

潜伏结核分枝杆菌感染免疫状态的多维分析

• 批准号: 9325427
• 负责人: Yueh-Hsiu Chien
• 金额: $ 19.75万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-03 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325427
• 关键词: 16 year old; AIDS/HIV problem; Adolescent; Adult; Age; Antibodies; Antigens; Area; B-Lymphocytes; BCG Vaccine; Bioinformatics; Biological Assay; Biological Process; Blood; Cells; Cessation of life; Characteristics; Child; Clinical; Cohort Studies; Collaborations; Computer Analysis; Cytometry; Data Set; Databases; Detection; Disease; Disease Outcome; Follow-Up Studies; Freezing; Frequencies; Gene Expression; Genetic Transcription; Genus Mycobacterium; Goals; Heavy Metals; Human; Immune; Immune response; Immune system; Immunity; Immunologics; Incidence; Individual; Infection; Interferon Type II; Intervention; Investigation; Isotope Labeling; Lead; Leukocytes; Link; Mass Spectrum Analysis; Measures; Mediating; Meta-Analysis; Microarray Analysis; Molecular Profiling; Mycobacterium tuberculosis; Natural Killer Cells; Neonatal; Opportunistic Infections; Pathway interactions; Patients; Pattern; Peripheral Blood Mononuclear Cell; Phenotype; Population; Preventive therapy; Progressive Disease; Pulmonary Tuberculosis; Research Design; Research Personnel; Sampling; Signal Transduction; South Africa; Symptoms; Systems Analysis; T-Lymphocyte; Techniques; Technology; Therapeutic; Time; Tuberculosis; Universities; Vaccines; age group; cell type; cohort; experimental study; high throughput analysis; immunological status; improved; insight; latent infection; mortality; novel; response; success; tool; transcriptome; transcriptome sequencing; vaccine candidate; γδ T cells

Summary/Abstract Active tuberculosis (TB) is a major cause of human death and disease. It is also the most common fatal opportunistic infection in HIV/AIDS worldwide. The current neonatal BCG vaccine does not provide notable protection against adult pulmonary TB and none of the vaccine candidates show efficacy in board and/or reliable protection against either infection or disease. Past studies have identified specific immune responses associated with protection. But simply boosting these responses as employed in most vaccine strategies was not sufficient to provide protection. Recent experiments indicate that persistent mycobacteria are in an active state, and that latent infection is maintained though an active immune response. A better understanding of how latent TB is controlled by the immune system is essential for developing therapeutic hypothesis that could open new avenues for clinical intervention. Other than transcriptional analysis, most studies of Mtb responses consist of targeted assays and a focus on either children or adult populations that show high disease rates. To better understand how latent TB is controlled, we have created a unique and powerful study design. First, we will use recently developed technologies, including mass cytometry (CyTOF) and RNAseq for broad, unbiased and high-throughput analyses. We will apply these powerful new techniques to a material collected from patients between 13-16 years old. This age group stratifies children and adults and is noted to be the “golden age” in TB where mortality and mobility is low. With this adolescent cohort, we hope to reduce the complexity inherent to latency, which can vary from something close to sterilizing immunity to subclinical active disease. In addition, we will employ bioinformatics tools to integrate and infer across two the cellular and transcriptome profiling proposed in Aim 1 and 2. Furthermore, we will use a novel integrated computationally analyses to compare our results with other TB studies from public database in Aim 3. Our goal is to gain new insight into how the course of Mtb infection is controlled in adolescents as compared with that from adults and children, and to identify factors that mediate and/or predict transitions from latent infection to active disease.

总结/摘要 活动性结核病（TB）是人类死亡和疾病的主要原因。它也是最常见的致命的 机会性感染艾滋病毒/艾滋病的世界各地。目前的新生儿BCG疫苗没有提供显著的 预防成人肺结核，并且没有候选疫苗显示出有效性和/或 对感染或疾病的可靠保护。过去的研究已经确定了特定的免疫反应 与保护有关。但是在大多数疫苗策略中， 不足以提供保护。最近的实验表明，持久性分枝杆菌是在一个活跃的 状态，并通过主动免疫应答维持潜伏感染。更好地了解如何 潜伏性结核病是由免疫系统控制的，这对于开发可能打开 临床干预的新途径。 除了转录分析之外，大多数Mtb应答研究包括靶向测定和重点分析。 无论是儿童还是成年人都显示出高发病率。为了更好地了解结核病的潜伏性 我们创造了一个独特而强大的研究设计。首先，我们将使用最近开发的 技术，包括质谱仪（CyTOF）和RNAseq，用于广泛，无偏倚和高通量 分析。我们将把这些强大的新技术应用于从13-16岁的患者中收集的材料 岁这个年龄组分为儿童和成人，被认为是结核病的“黄金年龄”， 死亡率和流动性低。通过这个青少年群体，我们希望减少延迟固有的复杂性， 其可以从接近于杀菌免疫的东西变化到亚临床活动性疾病。此外，我们会 采用生物信息学工具整合和推断两个细胞和转录组分析提出 目标1和2。此外，我们将使用一种新的综合计算分析来比较我们的结果 与目标3公共数据库中的其他结核病研究进行比较。我们的目标是获得新的见解如何结核病的过程中， 与成人和儿童相比，青少年的感染得到控制，并确定 介导和/或预测从潜伏感染到活动性疾病的转变。